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Total Synthesis of (+)-Omphadiol.

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DOI: 10.1002/anie.201102289
Total Synthesis
Total Synthesis of (+)-Omphadiol**
Gang Liu and Daniel Romo*
Omphadiol (1) is a sesquiterpene isolated from the basidiomycete omphalotus illudens and the edible fungus clavicorona
pyxidata (Scheme 1).[1] As a member of the africanane family
investigations into their likely biosynthetic interconnectivity.
Herein we report a three-step synthesis of a versatile,
carvone-derived bicyclic b-lactone, which constitutes the
key intermediate for the described ten-step synthesis of (+)omphadiol. This total synthesis also features several efficient
C C bond-forming reactions, novel single-pot, sequential and
tandem processes, and the highly stereocontrolled introduction of all six stereogenic centers.
Our synthetic strategy was premised on a late-stage
facially selective cyclopropanation of the C2 C4 double
bond governed by the topology of the [5.3.0] bicycle 6
(Scheme 2). The cycloheptenone would in turn be constructed
Scheme 1. (+)-Omphadiol and structurally related terpenes.
of sesquiterpenes, which all possess a 5-7-3 tricyclic core,
omphadiol contains six contiguous stereogenic centers, which
makes it a challenging synthetic target. Comparison with
structurally similar terpenoids, including pyxidatol (2) and
africanol (not shown),[2] reveals a large family of sesquiterpenes and diterpenes that share a common tetrasubstituted
cyclopentane ring (highlighted in red). Notably, many of these
natural products display potent biological activities. For
example, rossinone B (3) shows anti-inflammatory, antiviral,
and antiproliferative activities[3] while chinesin (4) possesses
antimicrobial and antiviral activity.[4] Tomoeone F (5) displays
significant cytotoxicity against KB cells.[5] While synthetic
studies toward members of this family including a recent
biomimetic synthesis of ( )-rossinone B have appeared,[6] no
further biological studies have been described. Full biological
evaluation of omphadiol was precluded owing to insufficient
quantities isolated from natural sources.[1a] As part of a
program to demonstrate the utility of b-lactones as synthetic
intermediates, we set out to develop a scaleable route to the
common cyclopentane core (highlighted in red) found in
these terpenoids as a prelude to biological studies and
[*] G. Liu, Prof. Dr. D. Romo
Department of Chemistry, Texas A&M University
P. O. Box 30012, College Station, TX 77842 (USA)
[**] The work was supported by the Welch Foundation (A-1280) and NSF
(CHE-0809747, partial). We thank Morgan Shirley for technical
assistance and Mikail Abbasov for performing calculations and
creating the graphic for the cover of this Issue. We thank Prof. Zheng
and Prof. Shen for providing the spectroscopic data of natural
Angew. Chem. Int. Ed. 2011, 50, 7537 –7540
Scheme 2. Retrosynthetic analysis of (+)-omphadiol from (R)-carvone via
the versatile bicyclic-b-lactone 9.
by ring-closing metathesis (RCM) of diene 7, which could be
derived from bromide 8 by a sequential one-pot intra-/
intermolecular dialkylation. The key intermediate for the
synthesis of omphadiol and related terpenes was identified as
the bicyclic b-lactone 9. We anticipated that this versatile
intermediate could be constructed by the reorganization of
the carbon skeleton of (R)-carvone through a nucleophilepromoted aldol lactonization process of a derived keto acid.
The synthesis of (+)-omphadiol commenced with a
(dpm = dipivaloylmethanato)
formal hydration of the enone moiety of (R)-carvone to
afford the hydroxy ketone 11 in a chemo- and regioselective
manner and as an inconsequential mixture of diastereomers
(d.r. 2:1; Scheme 3).[7] Subsequent oxidative cleavage of the
a-hydroxyketone by periodic acid delivered ketoacid 12.
Upon activation of the carboxylic acid with tosyl chloride, and
the addition of 4-PPY (4-pyrrolidinopyridine) as a nucleophilic promoter, ketoacid 12 underwent an aldol lactonization[8] to give the desired bicyclic b-lactone 9 with high
diastereoselectivity (55 %, d.r. > 19:1, as determined by
H NMR spectroscopy) after 24 hours, thus setting the first
C C bond (highlighted in red). Optimization studies revealed
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 3. Conversion of (R)-carvone into the versatile bicyclic-b-lactone 9 and bicyclic d-lactone 14. DIPEA = diisopropylethylamine,
DIBAl-H = diisobutylaluminium hydride, DMAP = 4-dimethylaminopyridine, dpm = dipivaloylmethanato, HMDS = hexamethyldisilazide,
PPY = 4-pyrrolidinopyridine, Ts = p-toluenesulfonyl.
that powdered anhydrous K2CO3, in combination with
iPr2NEt as a shuttle base,[9] led to a high yield (83 %) of blactone 9 in 2 hours on a scale greater than 10 g. The high
diastereoselectivity is rationalized by the chairlike transition
state 13, wherein the isopropenyl moiety adopts a pseudoequatorial position to avoid 1,3-allylic strain with the
ammonium enolate (E/Z geometry undefined) substituent
and developing 1,3-diaxial interaction (bonds highlighted in
The next stage of the synthesis required a four-carbon
homologation at C7, including the introduction of the C6gem-dimethyl moiety. Reduction of the b-lactone 9 gave the
corresponding diol that was converted into the corresponding
C7-bromide (Scheme 3). After numerous failed attempts to
form the C6 C7 bond using intermolecular alkylations with
various nucleophiles, we considered intramolecular variants.
Ultimately, a highly efficient process for construction of the
C6 C7 bond was identified, which involved a one-pot
tosylation/bromination sequence and a subsequent acylation
to provide ester 8. Treatment of this ester with KHMDS
(3 equiv) in THF at 78 8C, followed by quenching with
excess MeI, furnished the bicyclic d-lactone 14 bearing the
requisite C6 gem-dimethyl moiety. Thus, two required C C
bonds were formed in one operation. Notably, a dramatic and
unusual counterion effect was observed in this transformation, since LHMDS and NaHMDS gave only O-alkylation
products in the initial intramolecular alkylation.[10]
With ester 14 in hand, a two-step sequence involving the
reduction to the lactol and vinyl Grignard addition was
envisioned to introduce the remaining two carbon atoms
required for the ring-closing metathesis (RCM) to form
cycloheptene 17 (Scheme 4). While the degree of diastereoselectivity, if any, for the Grignard addition step was
uncertain, ester 14 was reduced to lactol 15 by DIBAl-H,
Scheme 4. Synthesis of 5-epi-omphadiol (inset: ORTEP representation
of the X-ray crystallographic structure of derivative 19; aryl groups
removed for clarity; thermal ellipsoids are shown at 50 % probability).[22] THF = tetrahydrofuran.
and to our surprise the subsequent addition of vinyl magnesium bromide gave diene 16 with high diastereoselectivity
(d.r. > 19:1, as determined by 1H NMR spectroscopy) even at
0 8C. The stereochemical outcome of this addition was
confirmed following conversion into 5-epi-omphadiol (18)
and by X-ray crystallographic analysis of ester 19. One
rationalization for this rare example of 1,5-stereoinduction[11]
invokes chelation control between an in situ generated C9magnesium alkoxide and the C5-aldehyde, thus leading to an
eight-membered metallocycle that imparts substantial facial
bias during nucleophilic addition. RCM of diene 16 using
Grubbs second generation catalyst[12] yielded the desired
trans-fused [5.3.0] bicyclic core in nearly quantative yield. A
Simmons–Smith cyclopropanation of allylic alcohol 17 gave
cyclopropane 18 with high diastereoselectivity (> 19:1).
However, comparison with NMR data reported for the
natural product suggested that a diastereomer had been
produced. X-ray crystallographic analysis of the bis(p-bromophenylester) derivative 19 unambiguously determined that
diol 18 was actually a C5 epimer of omphadiol. The high
diastereoselectivity obtained during the vinyl Grignard addition unfortunately led to the unnatural C5 diastereomer but
revealed an interesting example of 1,5-stereoinduction.
We recognized that one solution to the C5-stereochemical
issue would involve a facially selective reduction of enone 6,
which can be derived from the RCM of a dienone (cf. 7,
Scheme 2). The seemingly straightforward conversion of the
sterically hindered lactone 14 into enone 7 by the monoaddition of a vinylmetal species (e.g. vinyllithium, vinylmagnesium bromide, and divinylzinc), proved challenging. In
contrast to the facile partial reduction to lactol 15 by DIBAlH (Scheme 4) and numerous reported successful monoadditions of vinylmetal reagents to d-lactones, the monoaddition
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 7537 –7540
reaction with the sterically congested d-lactone 14 was
unsuccessful. The major by-product was derived from the
subsequent 1,4-conjugate addition to the initially formed a,benone 7.[13] Ultimately, this problem was circumvented by
addition of allyllithium, derived from allyltriphenyltin[14] by
transmetalation, to d-lactone 14 to give the b,g-enone 20
(Scheme 5). Use of the latter intermediate was premised on a
designed tandem isomerization/RCM process guided by the
known reluctance of RCM to provide eight-membered
rings[15] and the ability of the ruthenium–hydride species
generated from the Grubbs catalyst to promote olefin
isomerization.[16] As predicted, upon heating diene 20 with
the second generation Grubbs catalyst in toluene, the desired
cycloheptenone was formed in 95 % yield, thus indicating that
olefin isomerization was faster than RCM, a situation which
would have led to a cyclooctenone.
In summary, the first total synthesis of (+)-omphadiol has
been achieved in ten steps from (R)-carvone in an 18 %
overall yield. This synthesis features the highly stereocontrolled introduction of the six contiguous stereogenic centers
exclusively by using substrate control from the single
stereocenter in (R)-carvone. The concise nature of the
synthesis derives from a high ratio of C C bond-forming
steps (five of the ten steps) that proceed in a highly efficient
manner, the design and implementation of novel single-pot
sequential processes, and the absence of protecting groups.[21]
This total synthesis paves the way for further biological
studies of omphadiol and its congeners. Furthermore, synthetic strategies are now readily envisioned toward other
members of this class of terpenes by employing the versatile
bicyclic b-lactone 9, which can be readily prepared on a
multigram scale.
Received: April 1, 2011
Published online: July 14, 2011
Keywords: asymmetric synthesis · cyclopropanation ·
natural products · protecting group free · terpenoids
Scheme 5. Synthesis of (+)-omphadiol.
At this juncture, what remained to reach omphadiol was
the regio- and stereoselective reduction of the enone and a
facially selective cyclopropanation. After studying several
reaction conditions, enone 6 was reduced smoothly to give the
desired allylic alcohol 21 by treating with a DIBAl-H/tBuLi
complex at 78 8C in toluene (d.r. 14:1).[17] Finally, the
cyclopropanation of allylic alcohol 21 under Simmons–Smith
conditions gave (+)-omphadiol with high facial selectivity
(d.r. > 19:1). Despite the well-known directing effect of allylic
alcohols in seven-membered rings under Simmons–Smith
conditions,[18] this was not observed. This avoided the need for
protection of the C5-hydroxy group. The unique conformational constraint of allylic alcohol 21, imposed by the bicyclic
structure, places the secondary hydroxy group in a pseudoequatorial position (in plane with the p bond). This rigid
conformation is likely responsible for the unexpected, nonhydroxy directed but desired facial selectivity.[19 ] Both DFT
calculations[20] and NMR studies (JH4,H5 = 0 Hz) of alcohol 21
support the conformation shown in Scheme 5. Synthetic (+)omphadiol correlated well spectroscopically with the natural
product, including the optical rotation.
Angew. Chem. Int. Ed. 2011, 50, 7537 –7540
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[10] For a reversal of C- to O-alkylation with lithium enolates, see: P.
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[11] For an example using titanium(IV) reagents, see: a) K.
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2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[15] a) S. J. Miller, S.-H. Kim, Z.-R. Chen, R. H. Grubbs, J. Am.
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[19] To the best of our knowledge, this is the first example of
conformational constraint reversing the facial selectivity typically observed for cyclopropanations of 5- to 7-membered-ring
allylic alcohols, see: a) H. Lebel, J.-F. Marcoux, C. Molinaro,
A. B. Charette, Chem. Rev. 2003, 103, 977 – 1050; b) A. H.
Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307 –
1370; for a related cyclopropanation of a [5,7] bicyclic system,
see: c) J. Cossy, S. BouzBouz, M. Laghgar, B. Tabyaoui,
Tetrahedron Lett. 2002, 43, 823 – 827.
[20] A global minimum for allylic alcohol 21 was located by a Monte
Carlo (stochastic conformational) search using MOE (2008)
software followed by DFT/B3LYP/6-31 + (g) energy minimization with Gaussian 09M software.
[21] For a review describing protecting group free synthesis, see: I. S.
Young, P. S. Baran, Nat. Chem. 2009, 1, 193 – 205.
[22] CCDC 830937 (19) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
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